Design of Orally Active, Non-Peptidic Inhibitors of Human Leukocyte Elastase

Brown, Frederick J.; Andisik, Donald W.; Bernstein, Peter R; Bryant, Craig B.; Ceccarelli, C.; Damewood, James; Edwards, Philip D.; Earley, Roger A.; Feeney, Scott W.

doi:10.1021/jm00035a004

Cited by 61 publications

(39 citation statements)

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“…Because the methyl lithium was premixed with B 2 pin 2 to form the [B 2 pin 2 Me]Li complex, strongly nucleophilic/basic organometallic species were sequestered from the substrate: A gamut of functionalities such as ethers (30,31,35,37,41), esters (5,8,21,22,39,41), carbamates/ amides (1,8,15,28,36,37), ketones (34,38,39,40), olefins (39,40,41), and alcohol/phenol (40,41) were left unscathed under the mild reaction conditions. Indeed, even the highly basesensitive fluorenylmethyloxycarbonyl group was tolerated (see 8).…”

Section: Scope Of the Decarboxylative Borylation Reactionmentioning

confidence: 99%

Decarboxylative borylation

Wang

Barton

et al. 2017

Science

343

178

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INTRODUCTION The boronic acid is a functional group of enormous utility in materials science, chemosensor development, and drug discovery. In medicinal chemistry, boronic acids have been harnessed as a replacement for various structural motifs (a bioisostere) to improve the potency or pharmacokinetic profiles of lead compounds. However, the widespread incorporation of alkyl boronic acids has been largely hampered by the challenges associated with their preparation. Consequently, only two alkyl boronic acids are currently in clinical use, namely Velcade and Ninlaro. Few methods are capable of delivering alkyl boronates from readily available starting materials; most exhibit modest functional group compatibility. Indeed, boronate motifs are often installed at the early stage of a synthesis and thus consume disproportionate effort from the standpoint of planning and manipulation in multistep processes. RATIONALE Alkyl carboxylic acids, as the most variegated chemical building blocks on Earth, are present in a myriad of natural products and medicines. They represent an ideal precursor to boronic acids. Previous efforts from our laboratory revealed that, through the intermediacy of simple redox-active esters (RAEs, e.g., N-hydroxyphthalimide esters), alkyl carboxylic acids could be harnessed as convenient alkyl halide surrogates in metal-catalyzed decarboxylative cross-coupling reactions with carbon nucleophiles, using the same activating principles as amide bond formation. It was therefore surmised that such reactivity could be exploited in a decarboxylative borylation process wherein structurally diverse and ever-present carboxylic acids could be converted directly into high-value boronic acids. RESULTS Through the exclusive use of N-hydroxyphthalimide RAEs, a simple means to convert carboxylic acids into boronate esters was enabled with an inexpensive nickel catalyst. This reaction was broad in scope (>40 examples) and demonstrated excellent functional group compatibility (tolerating alkyl/aryl halides, amides/carbamates, alcohols, ketones, and olefins), and high levels of diastereoselectivity, allowing transformations of densely functionalized drug molecules (e.g., vancomycin and Lipitor) and natural products (e.g., enoxolone) into the analogous boronic acids. This method’s unique capacity to access α-amino boronic acids from native peptides not only allowed the concise syntheses of both Velcade and Ninlaro, it also enabled the expedient discovery of three highly potent human neutrophil elastase (HNE) inhibitors, the most potent of which has shown improved in vitro inhibitory activities (IC50 = 15 pM, Ki = 3.7 pM) relative to leading candidates previously tested in clinical trials. Enzymatic and pharmacokinetic studies indicated high functional stability in physiologically relevant media. CONCLUSION The nickel-catalyzed decarboxylative cross-coupling of RAEs enables substitution of ubiquitous alkyl carboxylic acids with boronate esters using an inexpensive boron source: B2pin2 (Bpin = pinacol boronate). Th...

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Section: Scope Of the Decarboxylative Borylation Reactionmentioning

confidence: 99%

Decarboxylative borylation

Wang

Barton

et al. 2017

Science

343

178

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“…Further optimizations of this series of derivatives were obtained by introducing a phenyl group at C6 of the pyridone nucleus and by varying length and chemical features of the N -terminal capping group, providing t-PFMKs with K i values in the low-nanomolar range. Concurrently, the same research group developed peptidomimetics containing other pyridone-based scaffolds such as pyrimidone, pyridopyrimidine, and β-carbolinone analogues, obtaining in some cases compounds with K i values in the sub-nanomolar range [ 117 ]. The most explored series was the pyrimidone-based one, in a comparative study with peptidomimetic analogues having boronic acid as the electrophilic warhead.…”

Section: Peptidyl Tri-fluoromethyl Ketones (T-pfmks)mentioning

confidence: 99%

Peptidyl Fluoromethyl Ketones and Their Applications in Medicinal Chemistry

Citarella

Micale

2020

Molecules

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Peptidyl fluoromethyl ketones occupy a pivotal role in the current scenario of synthetic chemistry, thanks to their numerous applications as inhibitors of hydrolytic enzymes. The insertion of one or more fluorine atoms adjacent to a C-terminal ketone moiety greatly modifies the physicochemical properties of the overall substrate, especially by increasing the reactivity of this functionalized carbonyl group toward nucleophiles. The main application of these peptidyl α-fluorinated ketones in medicinal chemistry relies in their ability to strongly and selectively inhibit serine and cysteine proteases. These compounds can be used as probes to study the proteolytic activity of the aforementioned proteases and to elucidate their role in the insurgence and progress on several diseases. Likewise, if the fluorinated methyl ketone moiety is suitably connected to a peptidic backbone, it may confer to the resulting structure an excellent substrate peculiarity and the possibility of being recognized by a specific subclass of human or pathogenic proteases. Therefore, peptidyl fluoromethyl ketones are also currently highly exploited for the target-based design of compounds for the treatment of topical diseases such as various types of cancer and viral infections.

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“…More progress in the oral bioavailability area was based on work done by workers at Zeneca who had successfully replaced the proline residue in their elastase inhibitors with either a pyridinone or a pyrimidinone ring [15]. Application of this principle to thrombin led to the pyridinone containing compound 11.…”

Section: Synthesis Of Inhibitors Of Hiv-rt and Thrombinmentioning

confidence: 99%